GH Resistance Is a Component of Idiopathic Short Stature: Implications for rhGH Therapy

Idiopathic short stature (ISS) is a term used to describe a selection of short children for whom no precise aetiology has been identified. Molecular investigations have made notable discoveries in children with ISS, thus removing them from this category. However, many, if not the majority of children referred with short stature, are designated ISS. Our interest in defects of GH action, i.e. GH resistance, has led to a study of children with mild GH resistance, who we believe can be mis-categorised as ISS leading to potential inappropriate management. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. The results are extremely variable. It is therefore important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as ‘ISS’.

IGF-1 and IGFBP-3 in Inflammatory Cachexia

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic–growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic–GH–IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

IGF-I/IGFBP3/ALS deficiency in sarcopenia: low GHBP suggests GH resistance in a subgroup of geriatric patients

Context Definition of etiological subgroups of sarcopenia may help to develop targeted treatments. Insulin like growth factor (IGF-I), IGF-binding protein 3 (IGFBP3) and acid labile subunit (ALS) build a ternary complex that mediates growth hormone (GH) effects on peripheral organs, such as muscle. Low GH binding protein (GHBP) as a marker of GH receptor number would hint towards GH resistance. Objective Analysis of the association of IGF-I, IGFBP3, and ALS with sarcopenia Study Participants and setting 131 consecutively recruited patients of a geriatric ward for a mono-center cross-sectional analysis, non-sarcopenic patients served as controls. Methods Sarcopenia status by hand grip strength measurement and Skeletal Muscle Index (SMI); IGF-I, IGFBP3, ALS, GH, GH binding protein (GHBP); body mass index (BMI), Activity of Daily Living (ADL), mini mental state test (MMST), routine laboratory parameters, statistical regression modelling. Results Compared to controls, sarcopenic patients did not differ regarding age, sex, ADL, MMST, C reactive protein, glomerular filtration rate and albumin serum concentrations. However, sarcopenic patients had significantly lower IGF-I, IGFBP3 and ALS. IGF I and ALS associated significantly with sarcopenia and low hand grip strength, even after adjustment for age, sex, BMI and albumin, but not with low SMI. GHBP serum was low in sarcopenic patients, but normal in geriatric patients without sarcopenia. Over 60% of patients with IGF-I/ALS deficiency patients showed GH resistance. Conclusions Our data suggest that in geriatric patients low IGF-I/IGFBP3/ALS could be evaluated for causative connection of the sarcopenia spectrum. Low GHBP points towards potential GH resistance as one possible explanation of this deficiency.

SOCS2 Silencing Improves Somatic Growth without Worsening Kidney Function in CKD

Background: Growth hormone (GH) resistance in CKD is partly due to increased expression of SOCS2, a GH signaling negative regulator. In SOCS2 absence, body growth is exaggerated. However, GH overexpression in mice causes glomerulosclerosis. Accordingly, we tested whether lack of SOCS2 improves body growth, but accelerates kidney damage in CKD. Methods: Eight-week-old mutant SOCS2-deficient high growth (HG) and normal wild-type mice (N) underwent 5/6 nephrectomy (CKD) or sham operation (C) and were sacrificed after 12 weeks, generating 4 groups: C-N, C-HG, CKD-N, CKD-HG. Results: Somatic growth, inhibited in CKD-N, increased significantly in CKD-HG. Liver p-STAT5, a key intracellular signal of GH receptor (GHR) activation, was decreased in CKD-N but not in CKD-HG. Serum Cr as well as histopathological scores of renal fibrosis were similar in both CKD groups. Kidney fibrogenic (TGF-β and collagen type IV mRNA) and inflammatory precursors (IL6, STAT3, and SOCS3 mRNA) were similarly increased in C-HG, CKD-HG, and CKD-N versus C-N. Renal GHR mRNA was decreased in C-HG, CKD-HG, and CKD-N versus C-N. Kidney p-STAT5 was decreased in CKD-N but not elevated in CKD-HG. Conclusions: CKD-related growth retardation is overcome by SOCS2 silencing, in association with increased hepatic STAT5 phosphorylation. Renal insufficiency is not worsened by SOCS2 absence, as kidney GHR and STAT5 are not upregulated. This may be due to elevated kidney proinflammatory cytokines and their mediators, phospho-STAT3 and SOCS3, which may counteract for the absence in SOCS2 and explain the renal safety of prolonged GH therapy in CKD.

Mini Review/Commentary: Growth Hormone Treatment in Children with Type 1 Diabetes

In the state of insulin deficiency, the growth hormone—insulin-like growth factor-I (GH–IGF-I) axis is altered due to hepatic GH resistance, which leads to GH hypersecretion and low circulating IGF-I concentration. On the other hand, both growth hormone deficiency (GHD) and GH excess have significant influence on carbohydrate metabolism. These complex interactions are challenging in diagnosing GHD in subjects with type 1 diabetes mellitus (T1DM) and in treating subjects with T1DM with GH. So far, there is only limited clinical experience in GH treatment in patients with T1DM, but recently first reports on metabolic safety and efficacy of GH treatment in subjects with T1DM have been published.

Effect of Growth Hormone and Calorie Restriction on the Expression of Antioxidant Enzymes in the Liver and Kidney of Growth Hormone Receptor Knockout Mice

Caloric restriction (CR) can delay aging and prolong life span and these actions may be related to reduced oxidative damage. Mice with disrupted growth hormone (GH) receptor/binding protein knockout (GHRKO) live significantly longer than their normal siblings. Therefore, it is of interest to examine the effects of chronic CR on hepatic and renal antioxidant enzymes as well as lipid peroxidation (LP) as an oxidative stress marker in GHRKO mice. Female GHRKO and normal mice were either fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age and examined at the age of 9 months. In the liver, catalase (CAT) activity was significantly increased in GHRKO-AL as compared to normal control -AL animals. CR reduced CAT activity in both GHRKO and normal phenotypes. Cu/Zn superoxide dismutase (SOD1) activity was also higher in GHRKO-AL as compared to normal-AL mice. However, CR reduced SOD1 activity in GHRKO mutants. Glutathione peroxidase (GPx) activity was significantly decreased in GHRKO-AL mice and further reduced in GHRKO-CR group of animals. CR significantly increased LP in GHRKOs while its activity was not altered in GHRKO-AL group of mice. In the kidney, CAT activity was lower in GHRKO-AL as compared to normal-AL, however CR did not induce any significant effect in both phenotypes. Similarly, SOD1 levels were significantly lower in GHRKO than in normal mice. GPx expression was higher in GHRKO-AL as compared to control-AL. CR reduced GPx activity in GHRKO mice but increased it in controls as compared to their AL counterparts. There was no difference in LP expression between GHRKO-AL and normal-AL mice. However, CR significantly increased its levels in both phenotypes. Although these findings do not support the hypothesis that CR would increase the capacity of ROS defense mechanisms in GHRKO mice by increasing antioxidant enzymes levels, they do agree with some of the reported effects of CR on their expression. We suspect that GH resistance and CR may affect aging by different mechanisms and if CR delays aging in GHRKO animals it is not due to changes in the activity of antioxidant enzymes.

Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-α and IL-1β in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.

Determinants of GH resistance in malnutrition

States of undernutrition are characterized by GH resistance. Decreased total energy intake, as well as isolated protein–calorie malnutrition and isolated nutrient deficiencies, result in elevated GH levels and low levels of IGF1. We review various states of malnutrition and a disease state characterized by chronic undernutrition – anorexia nervosa – and discuss possible mechanisms contributing to the state of GH resistance, including fibroblast growth factor 21 and Sirtuin 1. We conclude by examining the hypothesis that GH resistance is an adaptive response to states of undernutrition, in order to maintain euglycemia and preserve energy.